Divergent viral phosphodiesterases for immune signaling evasion

Doherty, Erin E.; Nomburg, Jason; Adler, Benjamin A.; Lopez, Santiago; Hsieh, Kendall; Price, Nathan; Blount, Nurashau; Doudna, Jennifer A.

doi:10.1016/j.chom.2025.10.018

Divergent viral phosphodiesterases for immune signaling evasion

Journal Article · Tue Nov 25 00:00:00 EST 2025 · Cell Host & Microbe

DOI:https://doi.org/10.1016/j.chom.2025.10.018· OSTI ID:3012833

^[1]; Nomburg, Jason ^[2]; Adler, Benjamin A. ^[1]; Lopez, Santiago ^[1]; Hsieh, Kendall ^[1]; Price, Nathan ^[3]; Blount, Nurashau ^[1]; Doudna, Jennifer A. ^[4]

University of California, Berkeley, CA (United States)
University of California, Berkeley, CA (United States); University of California, San Francisco, CA (United States). Gladstone Institutes; Austrian Academy of Sciences (ÖAW), Vienna (Austria)
University of California, Berkeley, CA (United States); University of California, San Francisco, CA (United States). Gladstone Institutes
University of California, Berkeley, CA (United States); University of California, San Francisco, CA (United States). Gladstone Institutes; Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)

Cyclic dinucleotides (CDNs) and other short oligonucleotides play fundamental roles in immune system activation in organisms ranging from bacteria to humans. In response, viruses use phosphodiesterase (PDE)-mediated oligonucleotide cleavage for immune evasion, a strategy whose diversity has not yet been explored. Here, we use a canonical 2H PDE (2H PDE) structure-based search of prokaryotic and eukaryotic viral sequences to identify an exceptional diversity of 2H PDEs across the virome, including enzymes not detectable with sequence search methods alone. Despite active site conservation, biochemical experiments reveal remarkable substrate specificity of these PDEs that corresponds to variations in the core 2H fold. This nuanced specificity allows 2H PDEs to selectively degrade oligonucleotide messengers to avoid interfering with host nucleotide signaling. Together, these findings nominate viral 2H PDEs as key regulators of CDN signaling across the tree of life.

View Accepted Manuscript (DOE)

Research Organization:: Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)

Sponsoring Organization:: National Institutes of Health (NIH); USDOE Office of Science (SC), Basic Energy Sciences (BES). Scientific User Facilities (SUF); USDOE Office of Science (SC), Biological and Environmental Research (BER)

Grant/Contract Number:: AC02-05CH11231; AC02-76SF00515

Other Award/Contract Number:: F32GM153031
P30GM133894
1S10OD020062-01

OSTI ID:: 3012833

Journal Information:: Cell Host & Microbe, Journal Name: Cell Host & Microbe Journal Issue: 12 Vol. 33; ISSN 1931-3128

Publisher:: ElsevierCopyright Statement

Country of Publication:: United States

Language:: English

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Divergent viral phosphodiesterases for immune signaling evasion

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